Polypeptides for restoring endothelial function and methods of use thereof
Inventors
Cheung-Flynn, Joyce • Brophy, Colleen M.
Assignees
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Publication Number
US-12583895-B2
Publication Date
2026-03-24
Expiration Date
Abstract
The present disclosure provides novel cell permeant polypeptides and pharmaceutical compositions thereof, and methods for using such polypeptides and pharmaceutical compositions for various therapeutic uses. The present disclosure more specifically provides polypeptides for restoring endothelial function.
Core Innovation
The invention provides chimeric, cell-permeant polypeptides (NiPp) for restoring endothelial function after injury. The polypeptides include a transduction domain (X1) fused to an endothelial-function domain (X2) derived from Niban/FAM129A, and the fusion is defined by a general formula X1-X2.
The endothelial-function domain (X2) is selected from polypeptide variants described as capable of restoring endothelial function. X2 includes Z3, where Z3 is selected from a phosphoserine or a phosphoserine analog, and the document provides specific combined sequences, including SEQ ID NO:1 (YARAAARQARASPAARRA(pS)AILPG).
The invention is presented as solving endothelial dysfunction and loss or restoration of endothelial function following injury, including stretch injury, acidosis/NS, ATP/BzATP injury, endoplasmic reticulum stress induced by tunicamycin, and cytokine-related contexts. The documented data indicate that NiPp restores endothelial relaxation responses and reduces p38 MAPK phosphorylation, including kinase activity associated with MSK1 and p38 MAPKα, with specificity described relative to appropriate controls.
Claims Coverage
The independent claim covers a method for restoring endothelial function by administering a polypeptide defined by a general formula X1-X2, incorporating a specified transduction domain (X1) and an endothelial-function domain (X2) that includes Z3 as phosphoserine or a phosphoserine analog. The claim contains four inventive features.
Administering a chimeric X1-X2 NiPp to restore endothelial function
A method for restoring endothelial function comprising administering to a subject in need thereof an effective amount of a polypeptide comprising an amino acid sequence according to the general formula X1-X2, where X1 comprises a transduction domain and X2 comprises a polypeptide capable of restoring endothelial function.
Using a specified transduction domain sequence as X1
X1 comprises a transduction domain, wherein the transduction domain comprises one of the listed sequences including GRKKRRORRRPPQ (SEQ ID NO:3), AYARAAARQARA (SEQ ID NO:4), and other specified transduction-domain sequences.
Selecting X2 endothelial-function polypeptide variants
X2 comprises a polypeptide capable of restoring endothelial function, wherein X2 is selected from the listed variants including SPAARRA (pS) AILPG (SEQ ID NO:24), SPARRA (pS) AILPG (SEQ ID NO:25), SPAARRV (pS) AILPG (SEQ ID NO:26), SPARRV (pS) AILPG (SEQ ID NO:27), SPAARGA (pS) AILPG (SEQ ID NO:28), SPARGA (pS) AILPG (SEQ ID NO:29), and other listed X2 variants.
Including Z3 as phosphoserine or a phosphoserine analog
X2 includes Z3, wherein Z3 is selected from a phosphoserine or a phosphoserine analog.
Overall, the claims cover administering an effective amount of a NiPp polypeptide defined by X1-X2, where X1 is chosen from specified transduction-domain sequences, X2 is chosen from listed endothelial-function restoring variants, and Z3 is specified as phosphoserine or a phosphoserine analog.
Stated Advantages
Restoring endothelial function after injury.
Restoring endothelial relaxation responses described in the document.
Reducing p38 MAPK phosphorylation, including MSK1 and p38 MAPKα, with specificity versus appropriate controls.
Documented Applications
Treatment of endothelial dysfunction in contexts including stretch injury, acidosis/NS, ATP/BzATP injury, tunicamycin ER stress, and cytokine contexts.
Targeting aging/longevity.
Targeting atherosclerosis and related cardiovascular conditions.
Targeting arterial stiffness/hypertension.
Targeting graft failure.
Targeting erectile dysfunction.
Targeting inflammatory diseases.
Targeting chronic pain.
Targeting cancer.
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